Abstract

Drug misuse represents a risk factor for cerebrovascular disease, especially among young people. Despite the fact that cannabis
is the most widely used illicit drug, there are only a few reports associating its use with cerebrovascular disease. We describe
a patient who suffered three ischaemic strokes immediately after cannabis consumption. Other stroke aetiologies were ruled
out, and neuroimaging revealed infarcts in different arterial areas as well as evidence of non-atherosclerotic arterial disease,
which suggests an underlying vasculopathy of uncertain (toxic or inflammatory) origin. Cannabis use may be associated with
ischaemic stroke in young patients, but its mechanism is unclear.

Drug misuse is a risk factor for stroke, especially among young people, and the substances most frequently implicated are
cocaine, heroin, amphetamines, and other sympathomimetic agents.1 Despite the fact that cannabis is the most widely consumed illicit drug worldwide, it has only exceptionally been associated
with cerebrovascular disease. We describe a patient with three recurrent strokes temporally related to hashish smoking.

CASE REPORT

A 36 year old primary school teacher, right handed, male, with no known vascular risk factors or migraine history, who had
consumed hashish sporadically in the past, developed, after an unusually heavy hashish consumption and 3–4 alcoholic drinks
at a party, an acute episode of isolated aphasia followed a few hours later by a convulsive seizure. He did not consume any
other illicit drugs or medication, and only sporadically consumed alcohol (2–3 drinks on occasional weekends).

The patient’s blood pressure was 120/80 mmHg on admission. Cranial MRI revealed two acute ischaemic infarcts, one over the
left temporal lobe, consistent with his neurological deficit, and another area of silent ischaemia in the right parietal lobe.
Magnetic resonance angiography (MRA) of the intracranial vasculature revealed a diminished calibre of the distal temporal
branches of the left middle cerebral artery (MCA) without involvement of its proximal segment (fig 1a). MRA of the extracranial
neck vasculature was normal, and no evidence of diffuse atherosclerotic disease was present. Urine toxicological screening
on admission was positive for cannabis and negative for amphetamines, cocaine, methadone, opiates, benzodiazepines, and barbiturates.
Serum glucose, creatinine, sodium, potassium, liver enzymes, blood count and differential, coagulation times, anticardiolipin
antibodies, lupus anticoagulant, C and S proteins, anti-thrombin III levels, erythrocyte sedimentation rate, C reactive protein,
venereal disease research laboratory slide test, HIV serology, and biochemical and microbiological cerebrospinal fluid examination
gave normal or negative results. Transoesophageal echocardiogram, including agitated saline administration and provocative
manoeuvres, was normal. Seizures did not recur and repeated electroencephalograms were normal; antiepileptic therapy was not
initiated.

(a) MR angiography of this patient after his first stroke. Arterial occlusion of the distal portions of the middle cerebral
artery can be seen (black arrows). (b–d) Axial FLAIR MRI sequences obtained after the last stroke. An acute ischaemic infarct
is observed over the right temporal and parietal lobes (b, open arrow). Old infarcts in an atrophic stage are also evident
(white arrows).

The patient was treated with ticlopidine. Despite therapy, and advice against drug consumption, he suffered another episode
of aphasia and right hemiparesis a year later, immediately after hashish smoking at another party. His blood pressure at the
emergency room was 140/80. Between the two episodes, he denied having consumed cannabis and he had been normotensive. MRI
disclosed an acute left frontal cortical infarction, responsible for his symptoms, as well as another area of silent acute
ischaemia over the contralateral frontal lobe. Repeated head and neck MRA studies did not reveal any additional abnormalities
compared with the first study; the known diminished calibre of the distal temporal branches of the left MCA was still present.
Again, a repeated diagnostic investigation gave only positive results for the presence of cannabis in urine.

The patient abstained from drug use for another 1½ years, then, after another heavy intake of hashish and 3–4 drinks of alcohol,
he suffered from auditory agnosia. His blood pressure was 110/75 mmHg on admission. MRI disclosed the presence of an acute
infarct involving the right posterior temporal and lower parietal lobes and evidenced previous infarcts (fig 1b–d). It disclosed
no new changes compared with the first study. The patient recovered and has since (2 years after the last stroke) remained
stable, on therapy with clopidogrel and denies further drug consumption.

DISCUSSION

Cannabis ingestion can result in a variety of side effects. The most frequent are psychiatric reactions, including behavioural
abnormalities and an increased risk of schizophrenia.2,3 Less known but no less important are its cardiovascular effects, which include tachycardia,4 hypertension, especially in decubitus,5 and postural hypotension.6 Carboxy-haemoglobin levels are also increased, thus decreasing the oxygen transportation capacity.7 Furthermore, cannabis increases the risk of myocardial infarction 4.8-fold during the hour following its intake8 and has been associated with paroxysmal atrial fibrillation,9 and there are reports of sudden death of cardiovascular origin following its consumption.10 Despite the fact that cannabis is the most consumed illicit drug, only 15 patients have so far been described with strokes
associated to cannabis consumption.11–21 In our patient the most relevant data were the presence of three repeated strokes in close temporal relationship with cannabis
and alcohol intake, involving different arterial territories in the absence of an embolic source or atherosclerotic disease,
and the favourable outcome after cessation of drug consumption.

Establishing a causal relationship between drug consumption and stroke is not easy, and this relationship is usually based
on a temporal link between drug use and the occurrence of stroke in young patients without any other vascular risk factors.
Because cannabis use is so widespread, this could represent a casual relationship; in fact, due to their high liposolubility
and persistence in fatty tissues, cannabis metabolites persist in urine for weeks and therefore, their presence in a patient
with a stroke could merely represent prior use. This patient’s case, however, is exceptional in that there was a close and
clearcut temporal relationship between drug intake and stroke, which occurred on three separate occasions. The repetition
of events after exposure to cannabis, previously undescribed, suggests a role for cannabis in this patient’s strokes. Alcohol
ingestion could also have contributed. The relationship between alcohol and ischaemic stroke is complex and whether binge
drinking is associated with stroke is controversial.22 Nevertheless, the role of alcohol in this patient’s strokes was probably secondary, as he did not consume large amounts of
the drug nor much higher levels than he was used to consuming occasionally on weekends. However, hashish is an illegal drug
in Spain, not subject to any regulation or control, and therefore other toxic substances could have been added during its
manufacture.

The mechanisms most frequently postulated in cannabis related stroke are vasospasm12–14 and postural hypotension with abnormal regulation of the brain blood flow.11,16,23 In our patient, there was no evidence of postural hypotension, and blood pressure measurements in the emergency room were
repeatedly normal. MRI angiography revealed a persistent mild decrease of the distal branches of the left MCA, which, together
with the involvement of multiple arterial territories, simultaneously suggests the existence of an underlying vasculopathy
of some sort. Some of the infarcts were not accompanied by arterial irregularities, but it is possible that these abnormalities
may be below the sensitivity threshold of MRI angiography and therefore go undetected. Conventional angiography might have
revealed a more diffuse damage or signs consistent with arteritis, but the patient refused it. On the other hand, the narrowing
of the branches of the left MCA persisted over the years, which argues against vasospasm in this patient.

Owing to the presence of multiple ischaemic infarcts, an embolic source was insistently pursued, and was ruled out on the
three admissions. However, paroxysmal atrial fibrillation can occur after cannabis consumption, and the simultaneous intake
of alcohol may predispose to weekend arrhythmias and stroke. Furthermore, recent studies have shown a high incidence of paroxysmal
atrial fibrillation in patients with stroke of idiopathic aetiology, mainly in patients with atrial septal abnormalities.24,25 Repeated electrocardiograms were normal upon arrival at the emergency room on the three different occasions; 24 hour Holter
and invasive heart electrophysiological studies to detect atrial vulnerability were not performed. Although the possibility
could not be ruled out completely that this patient’s strokes were of cardioembolic origin due to a paroxysmal atrial fibrillation
triggered by alcohol and cannabis consumption, and that MRA changes reflected a partial emboli recanalisation, the absence
of cardiac symptoms, the normality of the echocardiographic studies, and the absence of systemic embolic events make this
possibility unlikely. As mentioned, we believe that the most likely mechanism in this case was a vasculopathy, either toxic
or immune inflammatory, elicited by cannabis. Although there are no descriptions of cerebral vasculitis in cannabis users,
the presence of arteritis involving peripheral vessels has been described.26 Cannabis arteritis resembles Buerger’s disease, but in the first case patients are regular cannabis users and only moderate
tobacco smokers.26 Cannabis has a peripheral vasoconstrictor effect and its prolonged use could be an additive risk factor for juvenile and
young adult arteritis.26

Cannabis is not as safe a drug as many believe; it can be associated with ischaemic stroke in young people by unclear mechanisms,
and toxicological screening of patients with stroke should be performed and should include the determination of cannabinoids.
Future studies will be needed to clarify the role of cannabis as a stroke risk factor, as it could be underestimated. If this
was the case, cerebrovascular risk may increase in the future, due to an increased consumption based on the potential therapeutic
benefits of cannabis 27 and its possible legalisation in some countries.